Breast cancer is one of the greatest killers of women. Approximately 30-40% of all breast cancers are hormonally responsive. Ovariectomy appears to be the first method of choice in ablative therapy, but a number of remissions occur in addition to those produced by ovariectomy by the removal of the adrenal and pituitary glands. Our laboratory has observed that after the administration of a carcinogenic agent, dimethylbenzo-alpha-anthracene (DMBA), the stress induced by ether anesthesia and blood sampling, which releases both prolactin and ACTH, prevents tumorigenesis in some animals while in others it delays the onset of the disease (Gala and Loginsky, J. Nat. Cancer Inst. 51: 593, 1973). This proposal will study the endocrine factors mediating the inhibitory effect of stress on induced DMBA tumors. We will examine the influence of prolactin administration on steroid hormone output from the adrenal. We will study the influence of exogenous corticosterone and 18 OH deoxycorticosterone on prolactin secretion and on the induction of tumorigenesis after DMBA. The hormones will be administered under non-stressful conditions by adding them to the drinking water. We will also study the influence of altering the time of prolactin and corticosterone peaks on the induction of tumorigenesis. Animals will be injected with a long-acting estrogen, Estradurin, which results in daily prolactin surges. The influence of daily surges of both corticosterone and prolactin on incidence of induced mammary tumors will be studied. The action of estrogen on the mammary gland will be blocked using the antiestrogen Cl 628 which does not block estrogen's action on the CNS and on the prolactin surge. The effect of this hormonal regimen on induced tumorigenesis will be examined. The interval between the circadian peak in prolactin and corticosterone will be altered by hormonal injections and its involvement in mammary tumorigenesis will be studied. Other approaches will be examined to alter the interval between prolactin and corticosterone peaks such as changes in lighting schedules and feeding regimens and they will be studied as to their influence on DMBA-induced mammary tumors.